Quantitative Systems Pharmacology Model of Chimeric Antigen Receptor T-Cell Therapy

Abstract

Chimeric antigen receptor T-cell (CART) therapy is a new and promising cancer therapy. However, severe toxicity due to cytokine release syndrome (CRS) in CART-treated patients highlighted the possible danger of this new therapy. Disease burden and CART doses are the potential factors associated with CRS but the detail relationships between these factors and the severity of the CRS remain largely unknown. In this study, the quantitative systems pharmacology (QSP) approach is used to quantify the complex relationships among CART doses, disease burden, and pro inflammatory cytokines in human subjects and to gain relevant insights into the determinant of clinical toxicity/efficacy in development of CART therapy. The expansion of CART and elimination of B cells are more highly correlated with disease burden than the administered CART doses. To our best knowledge, this is the first QSP model that can describe the observed clinical data from CART-treated patients with cancer. This QSP model is a valuable tool for deepening our understanding of how the mechanism of action connects to the clinical outcomes and, therefore, may serve as an important model-based platform to guide the development and personalized dosing of the CART therapy.